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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/84—Nitriles
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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/62—Oxygen or sulfur atoms
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/73—Unsubstituted amino or imino radicals
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
  • C07D213/77—Hydrazine radicals
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/79—Acids; Esters
  • C07D213/80—Acids; Esters in position 3
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/81—Amides; Imides
  • C07D213/82—Amides; Imides in position 3

Definitions

• This invention relates to pyridine-2,3-diamines, their preparation, their salts, their use as intermediates and the use of some of them as cardiotonics.
• R 1 is lower-alkyl
• R 2 is hydrogen or lower-alkyl
• PY is 4- or 3- or 2-pyridinyl or 4- or 3- or 2-pyridinyl having one or two lower-alkyl substituents.
• the 3-amino-5-PY-2(1H)-pyridinones, 3-R 1 R 2 N-5-PY-2(1H)-pyridinones, the 1,2-dihydro-2-oxo-5-PY-2(1H)-nicotinonitriles and the 5-PY-2(1H)-pyridinones had cardiotonic activity; all others were intermediates as were the 1,2-dihydro-2-oxo-5-PY-2(1H)-nicotinonitriles and 5-PY-2(1H)-pyridinones.
• the invention relates to 2-R 3 RN-3-(R 1 R'N)-5-PY-6-Q-pyridines (I) or pharmaceutically-acceptable acid-addition salt thereof, which are useful as intermediates and/or as cardiotonic agents, where R 3 , R 1 , R, R', PY and Q are defined hereinbelow.
• the invention relates to the process which comprises the steps of reacting a 3-nitro-5-PY-6-Q-2(1H)-pyridinone (II) with an inorganic halogenating agent to produce a 2-halo-3-nitro-5-PY-6-Q-pyridine (III), reacting III with ammonia or an amine of the formula R 3 RNH (IV) to produce 2-R 3 RN-3-nitro-5-PY-6-Q-pyridine (V) and reducing V to produce 3-amino-2-R 3 RN-5-PY-6-Q-pyridine.
• Other process aspects of the invention relates to individual steps, i.e., II ⁇ III, III ⁇ V and V to I, and two-step combinations thereof, i.e., II ⁇ III ⁇ V and III ⁇ V ⁇ I.
• the invention in another process aspect, relates to the process which comprises the steps of reacting 5-PY-6-Q-2(1H)-pyridinone (VI) with an inorganic halogenating agent to produce 2-halo-5-PY-6-Q-pyridine (VII), reacting VII with ammonia or an amine of the formula R 3 RNH to produce 2-R 3 RN-5-PY-6-Q-pyridine (VIII), reacting VIII with a halogenating agent to produce 2-R 3 RN-3-halo-5-PY-6-Q-pyridine (IX) and reacting IX with R 1 R'NH to produce 2-R 3 RN-3-R 1 R'N-5-PY-6-Q-pyridine.
• process aspects of the invention relate to the above individual steps, i.e., VI ⁇ VII, VII ⁇ VIII, VIII ⁇ IX and IX ⁇ I, to the two-step combinations thereof, i.e., VI ⁇ VII ⁇ VIII, VII ⁇ VIII ⁇ IX and VIII ⁇ IX ⁇ I, and to the three-step combinations thereof, i.e., VI ⁇ VII ⁇ VIII ⁇ IX and VII ⁇ VIII ⁇ IX ⁇ I.
• composition of matter aspects of the invention are the above intermediates designated III, V, VII, VIII and IX or pharmaceutically-acceptable acid-addition salts thereof.
• a composition aspect of the invention relates to a cardiac composition for increasing cardiac contractility in a patient, said composition comprising a pharmaceutically-acceptable carrier and, as the active ingredient thereof, an effective amount of a cardiotonic 2-NRR-3-NR'R'-5-PY-6-Q-pyridine or 2-amino(or monomethylamino or dimethylamino)-5-PY-6-Q-pyridine or pharmaceutically-acceptable acid-addition salt thereof, where NRR and NR'R' are defined hereinbelow.
• the invention in a method aspect, relates to a method for increasing cardiac contractility in a patient requiring such treatment which comprises the administration of a medicament comprising a pharmaceutically-acceptable carrier and, as the active component thereof, an effective amount of the cardiotonic 2-NRR-3-NR'R'-5-PY-6-Q-pyridine or 2-amino (or monomethylamino or dimethylamino)-5-PY-6-Q-pyridine or pharmaceutically-acceptable acid-addition salt thereof.
• the invention resides in a 2-R 3 -RN-3-R 1 R'N-5-PY-6-Q-pyridine having the formula I ##STR1## or pharmaceutically-acceptable acid-addition salt thereof, where Q, R and R' are each hydrogen or lower-alkyl, PY is 4-or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, R 1 and R 3 are each hydrogen, lower-alkyl, lower-hydroxyalkyl, 2,3-dihydroxypropyl, lower-alkoxyalkyl or Y-NB where Y is lower-alkylene having at least two carbon atoms between its connecting linkages and NB is di-(lower-alkyl)amino or 4-morpholinyl.
• Preferred embodiments of the compounds of formula I are those where Q is hydrogen, methyl or ethyl, PY is 4-pyridinyl or 3-pyridinyl, R and R' are each hydrogen when one of R 1 or R 3 is hydrogen and the other of R 1 or R 3 is methyl, ethyl or 2-hydroxyethyl, or as cardiotonics, R 1 and R' are each hydrogen when R 3 is methyl or ethyl and R is hydrogen, methyl or ethyl.
• the invention resides in the process which comprises the steps of reacting a 3-nitro-5-PY-6-Q-2(1H)-pyridinone (II) with an inorganic halogenating agent to produce a 2-halo-3-nitro-5-PY-6-Q-pyridine (III), reacting the 2-halo compound (III) with ammonia or an amine of the formula R 3 RNH (IV) to produce 2-R 3 RN-3-nitro-5-PY-6-Q-pyridine (V) and reducing the 3-nitro compound (V) to produce 3-amino-2-R 3 RH-5-PY-6-Q-pyridine (I where R 1 is hydrogen), where PY, Q, R and R 3 have the meanings given above for formula I and halo is bromo or chloro.
• the invention resides in the process which comprises the steps of reacting 5-PY-6-Q-2(1H)-pyridinone (VI) with an inorganic halogenating agent to produce 2-halo-5-PY-6-Q-pyridine (VII), reacting the 2-halo compound (VII) with ammonia or an amine of the formula R 3 RNH to produce 2-(R 3 RN)-5-PY-6-Q-pyridine (VIII), reacting the latter (VIII) with a halogenating agent to produce 2-(R 3 RN)-3-halo-5-PY-6-Q-pyridine (IX) and reacting the 3-halo compound (IX) with ammonia or an amine of the formula R 1 R'NH to produce 2-(R 3 RN)-3-(R 1 R'N)-5-PY-6-Q-pyridine, where PY, Q, R, R', R 1 and R 3 have the meanings given above for formula I, 2-halo is bromo or chloro and 3-hal
• composition of matter aspects of the invention reside in above-noted 2-halo-3-nitro-5-PY-6-Q-pyridines (III), 2-(R 3 RN)-3-nitro-5-PY-6-Q-pyridines (V), 2-halo-5-PY-6-Q-pyridines (VII), 2-(R 3 RN)-5-PY-6-Q-pyridines (VIII) and 2-(R 3 RN)-3-halo-5-PY-6-Q-pyridines (IX), or pharmaceutically-acceptable acid-addition salts thereof, having the formulas ##STR2##
• a composition aspect of the invention resides in a cardiotonic composition for increasing cardiac contractility, said composition comprising a pharmaceutically-acceptable carrier and, as the active component thereof, an effective amount of a cardiotonic 2-NRR-3-NR'R'-5-PY-6-Q-pyridine (IA) or pharmaceutically-acceptable acid-addition salt thereof, where PY and Q have the meanings given for formula I and NRR and NR'R' are each amino, lower-alkylamino or di-(lower-alkyl)amino.
• IA cardiotonic 2-NRR-3-NR'R'-5-PY-6-Q-pyridine
• PY is 4-pyridinyl or 3-pyridinyl
• Q is hydrogen, methyl or ethyl
• NR'R' is amino
• NRR is amino, methylamino, ethylamino, dimethylamino or diethylamino.
• a method aspect of the invention resides in the method for increasing cardiac contractility in a patient requiring such treatment which comprises administering orally or parenterally in a solid or liquid dosage form to such patient an effective amount of a cardiotonic 2-NRR-3-NR'R'-5-PY-6-Q-pyridine (IA) or pharmaceutically-acceptable acid-addition salt thereof, where PY and Q have the meanings given for formula I and NRR and NR'R' are each amino, lower-alkylamino or di-(lower-alkyl)amino.
• IA cardiotonic 2-NRR-3-NR'R'-5-PY-6-Q-pyridine
• PY is 4-pyridinyl or 3-pyridinyl
• Q is hydrogen, methyl or ethyl
• NR'R' is amino
• NRR is amino, methylamino, ethylamino, dimethylamino or diethylamino.
• composition aspect of the invention resides in a cardiotonic composition for increasing cardiac contractility, said composition comprising a pharmaceutically-acceptable carrier and, as the active component thereof, an effective amount of a cardiotonic 2-amino(or monomethylamino or dimethylamino)-5-PY-6-Q-pyridine (VIII A) or pharmaceutically-acceptable acid-addition salt thereof, where Q is hydrogen or lower-alkyl and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents.
• PY is 4-pyridinyl or 3-pyridinyl and Q is hydrogen, methyl or ethyl.
• Another method aspect of the invention resides in the method for increasing cardiac contractility in a patient requiring such treatment which comprises administering orally or parenterally in a solid or liquid dosage form to said patient an effective amount of a cardiotonic 2-amino(or monomethylamino or dimethylamino)-5-PY-6-Q-pyridine (VIII A) or pharmaceutically-acceptable acid-addition salt thereof, where Q is hydrogen or lower-alkyl and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents.
• Preferred embodiments are those where PY is 4-pyridinyl or 3-pyridinyl and Q is hydrogen, methyl or ethyl.
• lower-alkyl as used herein, e.g., as one of the meanings for R, R', R 1 , R 3 or Q or as a substituent for PY in formula I, III, V, VII, VIII or IX, means alkyl radicals having from 1 to 6 carbon atoms which can be arranged as straight or branched chains, illustrated by methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, isobutyl, n-amyl, n-hexyl, and the like.
• PY in formula I, III, V, VII, VIII or IX where PY is 4-, 3- or 2-pyridinyl having 1 or 2 lower-alkyl substituents are the following: 2-methyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 3-methyl-4-pyridinyl, 2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl (alternatively named 2-methyl-5-pyridinyl), 2,3-dimethyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 2-ethyl-4-pyridinyl, 2-isopropyl-4-pyridinyl, 2-n-butyl-4-pyridinyl, 2-n-hexyl-4-pyridinyl, 2,6-diethyl-4-pyridinyl, 2,6-diethyl-3-pyridinyl, 2,6-diisopropyl-4-pyridinyl, 2,6-
• lower-hydroxyalkyl as used herein, e.g., for one of the meanings for R 1 or R 3 in formula I, means hydroxyalkyl radicals having from two to six carbon atoms which can be arranged as straight or branched chains and at least two carbon atoms of which separate hydroxy and the 2- or 3-amino-nitrogen atom attached to the pyridine ring, illustrated by 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxyamyl, 6-hydroxyhexyl, and the like.
• lower-alkoxyalkyl as used herein, e.g., for one of the meanings for R 1 or R 3 in formula I, means alkoxyalkyl radicals having form three to six carbon atoms which can be arranged as straight or branched chains and at least two carbon atoms of which separate the oxygen atom of alkoxyalkyl and the 2- or 3-amino-nitrogen atom attached to the pyridine ring, illustrated by 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 2-methoxypropyl, 2-methoxybutyl, 4-ethoxybutyl, 3-ethoxypropyl, 3-n-propoxypropyl, and the like.
• lower-alkylene designated as Y as part of R 1 or R 3 herein means lower-alkylene radicals having at least two carbon atoms between its connecting linkages and having from two to six carbon atoms which can be arranged as branched or straight chains, illustrated by ##STR3## and the like.
• the compounds of formula IA or VIIIA are useful both in the free base form and in the form of acid-addition salts, and, both forms are within the purview of the invention.
• the acid-addition salts are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the base form.
• the acids which can be used to prepare the acid-addition salts include preferably those which produce, when combined with the free base, pharmaceutically-acceptable salts, that is, salts whose anions are relatively innocuous to the animal organism in pharmaceutical doses of the salts, so that the beneficial cardiotonic properties inherent in the free base (IA or VIIIA) are not vitiated by side effects ascribable to the anions.
• salts with the scope of the invention are those derived from other mineral acids such as hydrobromic acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like, giving the hydrobromide, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, cyclohexylsulfamate and quinate, respectively.
• mineral acids such as hydrobromic acid, sulfuric acid, phosphoric acid and sulfamic acid
• organic acids such as acetic acid, citric acid,
• the acid-addition salts of said basic compound are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
• all acid-addition salts are within the scope of our invention. All acid-addition salts are useful as sources of the free base form even if the particular salt per se is desired as an intermediate product as for example when the salt is formed only for purposes of purification or identification, or when it is used as an intermediate in preparing a pharmaceutically-acceptable salt by ion exchange procedures.
• reaction of a 3-nitro-5-PY-6-Q-2(1H)-pyridinone or of a 5-PY-6-Q-2(1H)-pyridinone with an inorganic halogenating agent to produce a 2-halo-3-nitro-5-PY-6-Q-pyridine (III) or 2-halo-5-PY-6-Q-pyridine (VII) is preferably carried out by refluxing the 2(1H)-pyridinone with excess phosphorus oxychloride containing a catalytic amount of dimethylformamide to obtain the 2-chloro compound.
• Suitable inorganic halogenating agents include PCl 3 , POBr 3 , PBr 3 , PCl 5 , diphenylphosphoric dichloride, and the like. This reaction is further illustrated below in Examples A-1 through A-17 and B-1 through B-17.
• the reaction of the 2-halo compound (III or VII) with ammonia or an amine of the formula R 3 RNH to obtain V or VIII respectively, is run by heating the reactants, preferably under pressure using ammonia or source thereof and monomethylamine and at atmospheric pressure using the other higher primary amines, R 3 NH 2 or secondary amines, R 3 RNH.
• the reaction of III or VII with hydrazine is similarly run to obtain the corresponding 2-hydrazino derivatives, which are readily converted by reduction to the corresponding 2-amines. This reaction is further illustrated hereinbelow in Examples C-1 through C-29 and D-1 through D-9.
• reaction of V to obtain I where R 1 is hydrogen is preferably carried out by catalytic hydrogenation of V using a suitable catalyst, e.g., 10% palladium-on-charcoal, Raney nickel, and the like. This reaction is further illustrated below in Examples F-1 through F-30.
• the reaction of VIII with a halogenating agent to produce the corresponding 3-halo compound (IX) is preferably carried out using bromine to obtain the 3-bromo compound, chlorine to obtain the 3-chloro compound or iodine to obtain the 3-iodo compound.
• the 3-chloro compound (IX) can be obtained in two steps by first reacting 3-nitro-5-PY-6-Q-2(1H)-pyridinone with phenylphosphonic dichloride to produce 2,3-dichloro-5-PY-6-Q-pyridine and then selectively reacting the latter at the more reactive 2-chloro with R 3 RH 2 to produce IX.
• 2,3-dichloro-5-PY-6-Q-pyridine can be carried out by heating 3-nitro-5-PY-6-Q-2(1H)-pyridinone with phosphorus oxychloride in an autoclave. This reaction is further illustrated hereinbelow in Examples E-1 through E-3.
• reaction of IX with ammonia or an amine of the formula R 1 R'NH to produce I is carried out by heating the reactants as described above in the conversion of III to V or VII to VIII. This reaction is further illustrated below in Examples F-31 through F-41.
• hydrolysis of 1,2-dihydro-6-(lower-alkyl)-2-oxo-5-PY-nicotinonitrile to produce 1,2-dihydro-6-(lower-alkyl)-2-oxo-5-PY-nicotinic acid is conveniently run by heating the nitrile on a steam bath with an aqueous mineral acid, e.g., 50% sulfuric acid. This reaction is further illustrated below in Examples K-1 through K-11.
• the preparation of 1-PY-2(dimethylamino)ethenyl lower-alkyl ketone by reacting PY-methyl lower-alkyl ketone with dimethylformamide di-(lower-alkyl) acetal is carried out by mixing the reactants in the presence or absence of a suitable solvent.
• the reaction is conveniently run at room temperature, i.e., about 20°-25° C., or by warming the reactants up to about 100° C., preferably in a aprotic solvent, conveniently hexamethylphosphoramide because of the method used to prepare the PY-methyl lower-alkyl ketone, as noted below in Example C-1.
• reaction is further illustrated hereinbelow in Examples I-1 through I-11.
• the intermediate PY-methyl lower-alkyl ketones are generally known compounds which are prepared by known methods [e.g., as given in Rec. trav. chim 72, 522 (1953); U.S. Pat. No. 3,133,077 (5-12-64); Bull. Soc. Chim. France 1968, 4132; Chem. Abstrs. 79, 8539h (1973); Chem. Abstrs. 81, 120,401a (1974); J. Org. Chem. 39, 3834 (1974); Chem. Abstrs. 87, 6594q (1977); J. Org. Chem. 43, 2286 (1978)].
• the reaction of 1-PY-2-(dimethylamino)ethenyl lower-alkyl ketone with ⁇ -cyanoacetamide to produce 1,2-dihydro-2-oxo-5-PY-6-R-nicotinotrile is carried out preferably by heating the reactants in a suitable solvent in the presence of a basic condensing agent.
• the reaction is conveniently run using an alkali lower-alkoxide, preferably sodium methoxide or ethoxide, in dimethylformamide. In practicing the invention, the reaction was carried out in refluxing dimethylformamide using sodium methoxide.
• methanol and sodium methoxide or ethanol and sodium ethoxide can be used as solvent and basic condensing agent, respectively; however, a longer heating period is required.
• Other basic condensing agents and solvents include sodium hydride, lithium diethylamide, lithium diisopropylamide, and the like, in an aprotic solvent, e.g., tetrahydrofuran, acetonitrile, ether, benzene, dioxane, and the like. This reaction is further illustrated hereinbelow in Examples J-1 through J-11.
• Example A-1 Following the procedure of Example A-1 but using in place of 3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone a molar equivalent quantity of the appropriate 3-nitro-5-PY-6-Q-2(1H)-pyridinone (preparation of these compounds where Q is lower-alkyl is given hereinbelow in Examples L-1 through L-11, it is contemplated that the corresponding 2-chloro-3-nitro-5-PY-6-Q-pyridines of Examples A-2 through A-16 can be obtained.
• Example A-17 Following the procedure of Example A-1 but using in place of phosphorus oxychloride a molar equivalent quantity of phosphorus oxybromide or phosphorus tribromide, it is contemplated that the compound of Example A-17 can be obtained.
• Example B-2 Following the above procedure but using in place of phosphorus oxychloride a molar equivalent quantity of phosphorus oxybromide or phosphorus tribromide, it is contemplated that the corresponding compound of Example B-2 can be obtained.
• the corresponding 3-nitro-5-(4-pyridinyl)pyridine-2-hydrazine was prepared as follows: A mixture containing 10 g. of 2-chloro-3-nitro-5-(4-pyridinyl)pyridine, 50 ml. of hydrazine hydrate and 50 ml. of ethanol was refluxed for one hour and the ethanol and excess hydrazine-hydrate distilled off in vacuo. The residue was dissolved in water and reprecipitated with isopropyl alcohol, collected, washed with isopropyl alcohol and dried in vacuo at 70° C. to yield 7 g. of 3-nitro-5-(4-pyridinyl)pyridin-2-hydrazine.
• N-(2-Dimethylaminoethyl)-3-nitro-5-(4-pyridinyl)pyridin-2-amine alternatively named N-(2-dimethylaminoethyl)-5-nitro-[3,4'-bipyridin]-6-amine
• a solution containing 17 g. of 5-(4-pyridinyl)pyridin-2-amine in 200 ml. of acetic acid warmed to 70° C. was treated dropwise with 17.6 g. of bromine.
• the reaction mixture was heated at about 70°-75° C. for thirty minutes, allowed to cool and then diluted with ether.
• the precipitate was collected, washed with ether and dried.
• the solid was dissolved in water and the aqueous solution was basified with 2 N aqueous potassium hydroxide solution. The precipitate was collected, washed with water and dried and then recrystallized from ethanol and dried in vacuo at 70° C. to yield 14.5 g.
• the above product can be prepared by reducing the corresponding 3-nitro-5-(4-pyridinyl)pyridin-2-amine as follows: a mixture containing 27 g. of 3-nitro-5-(4-pyridinyl)pyridin-2-amine, 200 ml. of dimethylformamide and 2 g. of 10% palladium-on-charcoal was catalytically hydrogenated in a Parr apparatus for three and one-half hours at room temperature. The reaction mixture was filtered and the filtrate heated in vacuo to remove the solvent. The residue was combined with material obtained in another run starting with 10 g.
• a mixture containing 18.26 g. of 2-(2-dimethylaminoethylamino)-3-nitro-5-(4-pyridinyl)pyridine, 250 ml. of ethanol and 2.0 g. of 10% palladium-on-charcoal was hydrogenated by shaking in a Parr apparatus under catalytic hydrogenation conditions for seventy-two minutes at room temperature. The catalyst was filtered off and the filtrate was distilled in vacuo to remove the solvent. The residue was recrystallized from acetonitrile (final volume of 150 ml.) and dried at 70° C. in a vacuum oven over sixty hours to yield 13.4 g. of 3-amino-2-(2-dimethylaminoethylamino)-5-(4-pyridinyl)pyridine, m.p. 138°-141° C.
• F-7 3-Amino-2-(3-dimethylaminopropylamino)-5-(4-pyridinyl)pyridine.
• a mixture containing 22.6 g. of 2-(3-dimethylaminopropylamino)-3-nitro-5-(4-pyridinyl)pyridine, 250 ml. of ethanol and 2.0 g. of 10% palladium-on-charcoal was catalytically hydrogenated in a Parr apparatus for one and three-fourth hours at room temperature.
• the catalyst was filtered off and the filtrate was combined with the corresponding filtrate of an identical run except for a three hour hydrogenation period and the combined filtrates were concentrated in vacuo to remove the solvent.
• the residue was dissolved in hot acetonitrile (final volume of 200 ml.) and cooled. When no solid separated the acetonitrile solution was diluted to a volume of 500 ml.
• a mixture containing 33 g. of 2-amino-3-bromo-5-(4-pyridinyl)pyridine, 700 ml. of 40% aqueous methylamine, a pinch of copper-bronze metal and a pinch of cupric sulfate pentahydrate was autoclaved at 160° C. for sixty hours.
• the reaction mixture was filtered and the filtrate distilled in vacuo to remove the excess aqueous methylamine.
• the residue was slurried up in a minimum amount of cold water and the solid collected and dried.
• the solid was recrystallized twice from dimethylformamide, washed successively with ethanol and ether and dried in vacuo at 70° C. to yield 4 g. of 2-amino-3-methylamino-5-(4-pyridinyl)pyridine, m.p. 282°-285° C.
• F-36 2-Amino-3-(2,3-dihydroxypropylamino)-5-(4-pyridinyl)pyridine.
• Another 2.56 g. of green solid had not dissolved in the acetonitrile.
• the 5.15 g. portion of green solid was recrystallized from ethyl acetate (350 ml.) and dried at 90° C. in a vacuum oven for twenty hours to yield, as pale green prisms, 4.01 g. of 3-ethyl-1,3-dihydro-6-(4-pyridinyl)- 2H-imidazo[4,5-b]pyridin-2-one, m.p. 244°-246° C.
• the original 2.56 g. of insoluble green solid was recrystallized from ethyl acetate (150 ml.) and dried at 90° C. in vacuo to yield another 1.5 g. of product.
• the 4.01 g. and 1.51 g. portions of product were combined and dried in a vacuum oven at 100° C. for over sixty hours to yield 5.38 g. of said product, m.p. 244°-246
• G-7 1,3-Dihydro-3-[2-(4-morpholinyl)ethyl]-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.
• a mixture containing 15.11 g. of 3-amino-2-[2-(4-morpholinyl)ethylamino]-5-(4-pyridinyl)pyridine, 12.28 g. of carbonyldiimidazole and 300 ml. of dimethylformamide was stirred at 35° C. for over one hour and then stirred at room temperature for sixteen hours. The resulting suspension was stirred with heating at 75° C. for over seventy-five minutes. To the cooled solution was added another 8.11 g. portion of carbonyldiimidazole and the resulting mixture was stirred at about 35° C. for two and one-half hours, heated at about 75° C. for forty-five minutes, and to the reaction mixture was added 15 ml.
• Example G-9 thru G-26 Following the procedure described in Example G-2 but using in place of 3-amino-2-methylamino-5-(4-pyridinyl)pyridine a molar equivalent quantity of the appropriate 3-amino-2-R 3 NH-5-PY-6-Q-pyridine, it is contemplated that the 1,3-dihydro-3-R 3 -6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2-ones of Example G-9 thru G-26 can be obtained.
• G-36 1,3-Dihydro-1-(3-diethylaminopropyl)-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridin-2-one.
• the partially hydrated product was dissolved in 1 N aqueous potassium hydroxide solution and the mixture filtered through diatomaceous earth. The filtrate was neutralized with acetic acid, the solid collected, washed with water and dried in a vacuum over at 80° C. over the weekend (three days) to yield 8.5 g. of 1,3-dihydro-3-methyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridine-2-thione hydrate (3:1), m.p. >300° C.
• the solid was collected, washed with water, recrystallized twice from dimethylformamide, dried in a vacuum oven at 60° C. overnight to yield 50 g. of yellow powder.
• the yellow powder was slurried with 400 ml. of water and the aqueous mixture was made basic with 35% aqueous sodium hydroxide solution. The resulting solution was made acid with acetic acid, the precipitate was collected, washed with water and dried in a vacuum oven at 60° C. overnight to yield, as a pale yellow powder, 47 g. of 1,3-dihydro-3-methyl-6-(4-pyridinyl)-2H-imidazo[4,5-b]pyridine-2-thione hemihydrate, m.p. >300° C.
• G-7 1,3-Dihydro-1-(2-hydroxyethyl)-6-(4-pyridinyl)-2H-[4,5-b]pyridine-2-thione.
• hexamethylphosphoramide other solvents, e.g., dimethylformamide, acetonitrile or others noted above; however, hexamethylphosphoramide was conveniently used since (4-pyridinyl)methyl methyl ketone was conveniently prepared as a mixture together with hexamethylphosphoramide, as seen by the following preparation: To a stirred solution containing 70 cc. of freshly distilled diisopropylamine and 200 cc. of tetrahydrofuran at 0° C. under nitrogen was added dropwise over twenty minutes 210 cc.
• fraction III Examination of fraction III by NMR showed it to consist of a 2:3 mixture by weight of (4-pyridinyl)methyl methyl ketone and hexamethylphosphoramide.
• Acid-addition salts of 1-(4-pyridinyl)-2-dimethylamino)ethenyl methyl ketone are conveniently prepared by adding to a mixture of 5 g. of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone in about 100 ml. of aqueous methanol the appropriate acid, e.g., methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, to a pH of about 2 to 3, chilling the mixture after partial evaporation and collecting the precipitated salt, e.g., dimethanesulfonate, sulfate, phosphate, respectively.
• the appropriate acid e.g., methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid
• the acid-addition salt is conveniently prepared in aqueous solution by adding to water with stirring molar equivalent quantities each of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone and the appropriate acid, e.g., lactic acid or hydrochloric acid, to prepare respectively and the monoactate or monohydrochloride salt in aqueous solution.
• the appropriate acid e.g., lactic acid or hydrochloric acid
• the crystalline material was dissolved in carbon tetrachloride, cyclohexane was added and the mixture cooled to yield 64 g. of the resulting yellow crystalline product, 1(4-pyridinyl)-2-(dimethylamino)ethenyl ethyl ketone.
• Another 11 g. of crystalline product was obtained by passing the mother liquor through the continuous extraction column and using refluxing chloroform as the solvent.
• the crystalline product was collected, rinsed successively with acetonitrile and ether, and dried overnight at 55° C. to yield 28 g. of tan crystalline product, namely, sodium salt of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, the presence of cyano being confirmed by IR analysis.
• An 8 g. portion of said sodium salt was dissolved in 75 cc. of hot water, the aqueous solution treated with decolorizing charcoal filtered, the filtrate again treated with decolorizing charcoal and filtered, and the filtrate acidified with 6 N hydrochloric acid by dropwise addition to a pH of 3.
• the acidic mixture was diluted with ethanol and cooled.
• Acid-addition salts of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile are conveniently prepared by adding to a mixture of 2 g. of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile are conveniently prepared by adding to a mixture of 2 g. of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile in about 40 ml.
• aqueous methanol the appropriate acid, e.g., methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, to a small pH of about 2 to 3, chilling the mixture after partial evaporation and collecting the precipitated salt, e.g., dimethanesulfonate, sulfate, phosphate, respectively.
• the appropriate acid e.g., methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid
• the acid-addition salt is conveniently prepared in aqueous solution by adding to water with stirring molar equivalent quantities each of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile and the appropriate acid, e.g., lactic acid or hydrochloric acid, to prepare respectively the monolactate or monohydrochloride salt in aqueous solution.
• the appropriate acid e.g., lactic acid or hydrochloric acid
• Example D-2 Following the procedure described in Example D-2 but using a molar equivalent quantity of the appropriate 1-PY-2-(dimethylamino)ethenyl lower-alkyl ketone in place of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl ethyl ketone, it is contemplated that the corresponding 1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitriles of Examples J-3 thru J-17 can be obtained.
• Example C-1 Following the alternative procedure described in Example C-1 from line 59 of column 15 to line 2 of column 16 of U.S. Pat. No. 4,072,746 but using in place of 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile a molar equivalent quantity of the corresponding 1,2-dihydro-2-oxo-5-PY-6-(lower-alkyl)-nicotinonitrile, it is contemplated that there can be obtained the 5-PY-6-(lower-alkyl)-2(1H)-pyridinones of Examples M-1 through M-11.
• the compounds of formula IA or VIIIA or pharmaceutically-acceptable acid-addition salts thereof at doses of 1, 10, 30, and/or 100 ⁇ g./ml. were found to cause significant increases, that is, greater than 25% in papillary muscle force and significant increases, that is, greater than 25%, in right atrial force, while causing a lower percentage increase (about one-half or less than the percentage increase in right atrial force or papillary muscle force) in right atrial rate.
• the following preferred compounds were found to cause increases of 40% and greater in papillary muscle force and/or right atrial force: the compounds of Examples D-1, D-2, D-3, F-1, F-2, F-3, F-8 and F-9.
• the compounds of formula IA or VIIIA or pharmaceutically-acceptable acid-addition salts thereof at doses of 1.0, 3.0 and/or 10 mg/kg. administered intravenously were found to cause significant increases, that is, 25% or greater, in cardiac contractile force or cardiac contractility with lower changes in heart rate and blood pressure.
• the following preferred compounds were found to cause increases of 50% and greater in contractile force and lower changes in heart rate and blood pressure: the compounds of Examples D-1, D-2, F-3 and F-9.
• some embodiments of the compounds of formula IA or VIIIA or salts were found to have bronchodilator activity.
• the compounds of Examples F-8, D-1 and D-2 were each found to have bronchodilator activity by inhibiting bronchoconstriction induced by histamine, acetylcholine or immune complex in guinea pigs.
• the present invention includes within its scope a cardiotonic composition for increasing cardiac contractility, said composition comprising a pharmaceutically-acceptable carrier and, as the active component thereof, the cardiotonic compound of formula IA or VIIIA or pharmaceutically-acceptable acid-addition salt thereof.
• the invention also includes within its scope the method for increasing cardiac contractility in a patient requiring such treatment which comprises administering to such patient an effective amount of cardiotonic compound of formula IA or VIIIA or pharmaceutically-acceptable acid-addition salt thereof.
• said compound or salt thereof will normally be administered orally or parenterally in a wide variety of dosage forms.
• Solid compositions for oral administration include compressed tablets, pills, powders and granules.
• at least one of the active compounds is admixed with at least one inert diluent such as starch, calcium carbonate, sucrose or lactose.
• inert diluents such as starch, calcium carbonate, sucrose or lactose.
• These compositions can also contain additional substances other than inert diluents, e.g., lubricating agents, such as magnesium stearate, talc and the like.
• Liquid compositions for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water and liquid paraffin. Besides inert diluents such compositions can also contain adjuvants, such as wetting and suspending agents, and sweetening, flavoring, perfuming and preserving agents. According to the invention, the compounds for oral administration also include capsules of absorbable material, such as gelatin, containing said active component with or without the addition of diluents or excipients.
• Preparations according to the invention for parenteral administration include sterile aqueous, aqueous-organic, and organic solutions, suspensions and emulsions.
• organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate.
• These compositions can also contain adjuvants such as stabilising, preserving, wetting, emulsifying and dispersing agents.
• They can be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporation of sterilising agents in the compositions, by irradiation or by heating. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
• the percentages of active component in the said composition and method for increasing cardiac contractility can be varied so that a suitable dosage is obtained.
• the dosage administered to a particular patient is variable, depending upon the clinician's judgement using as the criteria: the route of administration, the duration of treatment, the size and condition of the patient, the potency of the active component and the patient's response thereto.
• An effective dosage amount of active component can thus only be determined by the clinician considering all criteria and utilizing the best judgement on the patient's behalf.

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